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Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Auriculasin sensitizes primary prostate cancer CT99021 to TRAIL-mediated T apoptosis through up-regulation of the DR5-dependent pathway
Hyun-Dong Choa, In-Ah Gub, Yeong-Seon Wonc, Kwang-Deog Moona, Ki-Hun Parkd, Kwon-Il Seoe,∗ a Department of Food Science and Technology, Kyungpook National University, Daegu, 41566, Republic of Korea
b Department of Food Science, University of Arkansas, AR, 72704, USA
c Institute of Agriculture Life Science, Dong-A University, Busan, 49315, Republic of Korea
d Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju, 52828, Republic of Korea
e Department of Biotechnology, Dong-A University, Busan, 49315, Republic of Korea
Death receptor 5
Primary prostate cancer
Tumor necrosis factor-related apoptosis-inducing ligand
Primary prostate cancer cells frequently develop resistance toward chemotherapy as well as most chemother-apeutics have been reported to induce undesirable cytotoxicity in normal cells. In this study, we performed sensitizing activity analysis of auriculasin (AC) to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in RC-58T/h/SA#4 primary prostate cancer cells without significant cytotoxicity in RWPE-1 prostate epithelial cells. Combined treatment with AC and TRAIL at optimal concentrations resulted in tumor-specific apoptotic cell death in RC-58T/h/SA#4 cells, characterized by DNA fragmentation, accumulation of apoptotic cell population, and nuclear condensation. Compared to single treatment with AC or TRAIL, co-treatment with AC and TRAIL significantly increased expression of Bax, cleaved PARP, AIF, endo G, and cytochrome c but decreased expression of phosphorylation of AKT and mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K), Bcl-2 and caspases-9, -8, -3, and -10. The sensitizing eﬀect of AC to TRAIL was well correlated with inhibition of death receptor 5 (DR5) CHOP, and p53 expression. Moreover, pre-treatment with a chimeric blocking antibody for DR5 eﬀectively reduced AC-TRAIL-induced cell death and apoptosis-related protein ex-pression. These results suggest that non-toxic concentrations of AC sensitize TRAIL-resistant primary prostate cancer cells to TRAIL-mediated apoptosis via up-regulation of DR5 and downstream signaling pathways.
Numerous cancer species are characterized by extremely aggressive growth in early stages of development to nearby and distant organs (Massagué and Obenauf, 2016). Thus, failure to treat primary cancer at an early stage can increase morbidity and mortality of prostate cancer patients (Berger et al., 2011). In recent years, eﬀective cancer strategies applying chemotherapeutics to cancer stem cells or primary cancer cells have attracted attention (Zhang et al., 2018; Zhang et al., 2018). However, drug resistance and normal cell toxicity are known as major hurdles in early stages of primary cancer therapy. Since primary and metastases cancer cells show molecular diﬀerences (Ramaswamy et al., 2003), it is also urgent to articulate novel therapeutic strategies for primary prostate cancer with minimal cytotoxicity in normal cells.